腫瘤血管正常化透過抑制腫瘤血管新生改善血管成熟度，修復血流灌注能力和氧合作用，提升藥物遞送與腫瘤治療的效果。抗血管新生藥劑（例如Avastin）可藉由減少血管內皮生長因子（VEGF）的表現，產生短暫的血管正常化效果，其時間窗為3-7天。超音波刺激帶氧微氣泡（O2-MBs）局部釋放O2，可減少缺氧誘導因子-1α（HIF-1α）的表現，降低腫瘤缺氧導致的治療抗性。由於氧氣敏感酵素（PHD2）在常氧狀況下會被活化，促使HIF-1α被降解，進而限制VEGF的表現，這提出了透過調節VEGF的上游因子，來誘發血管正常化的可行性。因此，我們透過超音波結合O2-MBs，評估於腫瘤區域局部釋放氧氣，誘發血管正常化的可行性。由C3F8和O2氣體體積比為7：5製作而成的O2-MB，平均直徑為1.02±0.03μm，溶氧量為8.90±0.02 mg/L。皮下攝護腺癌小鼠靜脈注射2×107 O2-MBs後，透過超音波（2-MHz，2 MPa，1000 cycle，PRF為2 Hz）刺激O2-MBs在腫瘤內局部釋放O2（O2-MBs +US），並於治療前後以超音波對比影像追蹤腫瘤血流灌注，評估血管正常化是否發生。在O2-MBs給予的第4天，量測腫瘤內PHD2、HIF-1α、VEGF的表現量，以推測O2-MBs誘發血管正常化的可能途徑。最後，以組織切片染色分析血管密度（CD31）、周細胞覆蓋率（α-SMA）和血管擴散能力（Hoechst33342）。結果發現O2-MBs +US組的腫瘤血流灌注於給氧後第2-8天，相較於控制組皆有顯著提升。O2-MBs+US組的PHD2、HIF-1α和VEGF表現量相較於控制組分別減少了60±16%、55±21%和47±8%。此外，O2-MBs+US組的血管成熟度和血管擴散能力也比控制組高2.4±0.5和1.5±0.2倍。我們的研究證明了使用O2-MBs於腫瘤中局部釋放氧氣，可調控上游因子PHD2與HIF-1α去抑制VEGF的表達，進而誘發腫瘤血管正常化，其時間窗為給O2後的2-8天。

Tumor vascular normalization (VN) promotes blood perfusion and oxygenation by improving vessel maturity under the inhibition of angiogenesis. Anti-angiogenic agents (e.g. Avastin) reduces the secretion of vascular endothelial growth factor (VEGF) to improve the efficiency of drug delivery within a transient “time window” of VN (typically 3–7 days). Ultrasound-stimulated oxygen-microbubbles (O2-MBs+US) can locally release O2 to address tumor hypoxia. The degradation of hypoxia-inducible factor-1α (HIF-1α) under the normoxic condition by O2 sensor prolyl-hydroxylase 2 (PHD2) activation would restrict VEGF secretion, which provides a potentiality to accomplish VN by regulating the upstream pathway of VEGF. Therefore, our study investigated the feasibility of VN induced by O2-MBs+US. The mean diameter and O2 concentration of O2-MBs (C3F8: O2=7:5 in volume ratio) was 1.02±0.03 μm and 8.90±0.02 mg/L, respectively. Tumor-bearing mice were intravenously injected 2×107 O2-MBs to locally release O2 within tumors by US sonication (2-MHz, 2 MPa, 1000 cycles, PRF of 2 Hz, 20 min for whole tumor scanning). Because tumor perfusion is an important index for VN outcome, tumor perfusion was estimated over time. To unravel the probable pathway of VN process, the expressions of PHD2, HIF-1α, and VEGF with tumors were evaluated by Western blot at day 4 after O2-MBs+US. The histological experiments of solid tumors were also introduced to calculate the ratio of vessel density (CD31), pericyte coverage (α-SMA) and perfused vessel (Hoechst33342). Tumor perfusion was increased at 2–8 days in the O2-MBs+US group with respect to the control group. Comparison with the control group, the reduction of 60±16%, 55±21%, and 47±8% in PHD2, HIF-1α, and VEGF expression, respectively, certified the regulation of VEGF upstream pathway by O2 release. Moreover, vessel maturity and Hoechst intensity in the O2-MBs+US group was 2.4±0.5-fold and 1.5±0.2-fold higher than the control group, individually. Our study demonstrated that local release of O2 in tumors can regulate PHD2 and Hif-1α to restrict VEGF expression, which induced VN within a time window of 2-8 days.

[1] H. F. Dvorak, V. M. Weaver, T. D. Tlsty, and G. Bergers, "Tumor microenvironment and progression," J Surg Oncol, vol. 103, pp. 468-74, May 1 2011.
[2] K. Hede, "Environmental protection: studies highlight importance of tumor microenvironment," J Natl Cancer Inst, vol. 96, pp. 1120-1, Aug 4 2004.
[3] S. Y. Sung and L. W. Chung, "Prostate tumor-stroma interaction: molecular mechanisms and opportunities for therapeutic targeting," Differentiation, vol. 70, pp. 506-21, Dec 2002.
[4] A. L. Harris, "Hypoxia--a key regulatory factor in tumour growth," Nat Rev Cancer, vol. 2, pp. 38-47, Jan 2002.
[5] J. R. Mackey, R. S. Kerbel, K. A. Gelmon, D. M. McLeod, S. K. Chia, D. Rayson, et al., "Controlling angiogenesis in breast cancer: a systematic review of anti-angiogenic trials," Cancer Treat Rev, vol. 38, pp. 673-88, Oct 2012.
[6] P. Carmeliet and R. K. Jain, "Angiogenesis in cancer and other diseases," Nature, vol. 407, pp. 249-57, Sep 14 2000.
[7] F. Nussenbaum and I. M. Herman, "Tumor angiogenesis: insights and innovations," J Oncol, vol. 2010, p. 132641, 2010.
[8] P. Carmeliet, "Mechanisms of angiogenesis and arteriogenesis," Nat Med, vol. 6, pp. 389-95, Apr 2000.
[9] S. M. Weis and D. A. Cheresh, "Tumor angiogenesis: molecular pathways and therapeutic targets," Nat Med, vol. 17, pp. 1359-70, Nov 7 2011.
[10] S. M. Weis and D. A. Cheresh, "Pathophysiological consequences of VEGF-induced vascular permeability," Nature, vol. 437, pp. 497-504, Sep 22 2005.
[11] H. Gerhardt and C. Betsholtz, "Endothelial-pericyte interactions in angiogenesis," Cell Tissue Res, vol. 314, pp. 15-23, Oct 2003.
[12] K. A. Krohn, J. M. Link, and R. P. Mason, "Molecular imaging of hypoxia," J Nucl Med, vol. 49 Suppl 2, pp. 129S-48S, Jun 2008.
[13] S. Kizaka-Kondoh, M. Inoue, H. Harada, and M. Hiraoka, "Tumor hypoxia: a target for selective cancer therapy," Cancer Sci, vol. 94, pp. 1021-8, Dec 2003.
[14] G. L. Semenza, "HIF-1 and tumor progression: pathophysiology and therapeutics," Trends Mol Med, vol. 8, pp. S62-7, 2002.
[15] B. A. Teicher, S. A. Holden, A. Alachi, and T. S. Herman, "Classification of Antineoplastic Treatments by Their Differential Toxicity toward Putative Oxygenated and Hypoxic Tumor Subpopulations Invivo in the Fsaiic Murine Fibrosarcoma," Cancer Research, vol. 50, pp. 3339-3344, Jun 1 1990.
[16] J. M. Brown and W. R. Wilson, "Exploiting tumour hypoxia in cancer treatment," Nat Rev Cancer, vol. 4, pp. 437-47, Jun 2004.
[17] J. M. Brown, "Exploiting the hypoxic cancer cell: mechanisms and therapeutic strategies," Mol Med Today, vol. 6, pp. 157-62, Apr 2000.
[18] T. P. Padera, B. R. Stoll, J. B. Tooredman, D. Capen, E. di Tomaso, and R. K. Jain, "Pathology: cancer cells compress intratumour vessels," Nature, vol. 427, p. 695, Feb 19 2004.
[19] J. Cassavaugh and K. M. Lounsbury, "Hypoxia-mediated biological control," J Cell Biochem, vol. 112, pp. 735-44, Mar 2011.
[20] G. L. Semenza, "Targeting HIF-1 for cancer therapy," Nat Rev Cancer, vol. 3, pp. 721-32, Oct 2003.
[21] M. W. Dewhirst, Y. Cao, and B. Moeller, "Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response," Nat Rev Cancer, vol. 8, pp. 425-37, Jun 2008.
[22] J. A. Bertout, S. A. Patel, and M. C. Simon, "The impact of O2 availability on human cancer," Nat Rev Cancer, vol. 8, pp. 967-75, Dec 2008.
[23] Q. Ke and M. Costa, "Hypoxia-inducible factor-1 (HIF-1)," Mol Pharmacol, vol. 70, pp. 1469-80, Nov 2006.
[24] G. L. Wang, B. H. Jiang, E. A. Rue, and G. L. Semenza, "Hypoxia-Inducible Factor-1 Is a Basic-Helix-Loop-Helix-Pas Heterodimer Regulated by Cellular O-2 Tension," Proceedings of the National Academy of Sciences of the United States of America, vol. 92, pp. 5510-5514, Jun 6 1995.
[25] C. J. Schofield and P. J. Ratcliffe, "Oxygen sensing by HIF hydroxylases," Nat Rev Mol Cell Biol, vol. 5, pp. 343-54, May 2004.
[26] P. Carmeliet, Y. Dor, J. M. Herbert, D. Fukumura, K. Brusselmans, M. Dewerchin, et al., "Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis," Nature, vol. 394, pp. 485-90, Jul 30 1998.
[27] N. C. Denko, "Hypoxia, HIF1 and glucose metabolism in the solid tumour," Nat Rev Cancer, vol. 8, pp. 705-13, Sep 2008.
[28] A. I. Minchinton and I. F. Tannock, "Drug penetration in solid tumours," Nat Rev Cancer, vol. 6, pp. 583-92, Aug 2006.
[29] J. H. Distler, R. H. Wenger, M. Gassmann, M. Kurowska, A. Hirth, S. Gay, et al., "Physiologic responses to hypoxia and implications for hypoxia-inducible factors in the pathogenesis of rheumatoid arthritis," Arthritis Rheum, vol. 50, pp. 10-23, Jan 2004.
[30] H. Zhong, A. M. De Marzo, E. Laughner, M. Lim, D. A. Hilton, D. Zagzag, et al., "Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases," Cancer Res, vol. 59, pp. 5830-5, Nov 15 1999.
[31] K. L. Talks, H. Turley, K. C. Gatter, P. H. Maxwell, C. W. Pugh, P. J. Ratcliffe, et al., "The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages," Am J Pathol, vol. 157, pp. 411-21, Aug 2000.
[32] O. Iliopoulos, A. P. Levy, C. Jiang, W. G. Kaelin, Jr., and M. A. Goldberg, "Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein," Proc Natl Acad Sci U S A, vol. 93, pp. 10595-9, Oct 1 1996.
[33] R. Ravi, B. Mookerjee, Z. M. Bhujwalla, C. H. Sutter, D. Artemov, Q. W. Zeng, et al., "Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1 alpha," Genes & Development, vol. 14, pp. 34-44, Jan 1 2000.
[34] W. Zundel, C. Schindler, D. Haas-Kogan, A. Koong, F. Kaper, E. Chen, et al., "Loss of PTEN facilitates HIF-1-mediated gene expression," Genes Dev, vol. 14, pp. 391-6, Feb 15 2000.
[35] J. Folkman, "Anti-angiogenesis: new concept for therapy of solid tumors," Ann Surg, vol. 175, pp. 409-16, Mar 1972.
[36] M. E. Eichhorn, S. Strieth, and M. Dellian, "Anti-vascular tumor therapy: recent advances, pitfalls and clinical perspectives," Drug Resist Updat, vol. 7, pp. 125-38, Apr 2004.
[37] R. K. Jain, "Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy," Nat Med, vol. 7, pp. 987-9, Sep 2001.
[38] P. V. Dickson, J. B. Hamner, T. L. Sims, C. H. Fraga, C. Y. Ng, S. Rajasekeran, et al., "Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy," Clin Cancer Res, vol. 13, pp. 3942-50, Jul 1 2007.
[39] T. L. Sims, M. McGee, R. F. Williams, A. L. Myers, L. Tracey, J. B. Hamner, et al., "IFN-beta restricts tumor growth and sensitizes alveolar rhabdomyosarcoma to ionizing radiation," Mol Cancer Ther, vol. 9, pp. 761-71, Mar 2010.
[40] M. Franco, S. Man, L. Chen, U. Emmenegger, Y. Shaked, A. M. Cheung, et al., "Targeted anti-vascular endothelial growth factor receptor-2 therapy leads to short-term and long-term impairment of vascular function and increase in tumor hypoxia," Cancer Res, vol. 66, pp. 3639-48, Apr 1 2006.
[41] P. P. Wong, N. Bodrug, and K. M. Hodivala-Dilke, "Exploring Novel Methods for Modulating Tumor Blood Vessels in Cancer Treatment," Curr Biol, vol. 26, pp. R1161-R1166, Nov 7 2016.
[42] S. Goel, D. G. Duda, L. Xu, L. L. Munn, Y. Boucher, D. Fukumura, et al., "Normalization of the vasculature for treatment of cancer and other diseases," Physiol Rev, vol. 91, pp. 1071-121, Jul 2011.
[43] P. Vaupel, "The role of hypoxia-induced factors in tumor progression," Oncologist, vol. 9 Suppl 5, pp. 10-7, 2004.
[44] P. Carmeliet and R. K. Jain, "Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases," Nat Rev Drug Discov, vol. 10, pp. 417-27, Jun 2011.
[45] S. Koyama, S. Matsunaga, M. Imanishi, Y. Maekawa, H. Kitano, H. Takeuchi, et al., "Tumour blood vessel normalisation by prolyl hydroxylase inhibitor repaired sensitivity to chemotherapy in a tumour mouse model," Sci Rep, vol. 7, p. 45621, Mar 31 2017.
[46] P. Baluk, S. Morikawa, A. Haskell, M. Mancuso, and D. M. McDonald, "Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors," Am J Pathol, vol. 163, pp. 1801-15, Nov 2003.
[47] E. C. Tsilibary, "Microvascular basement membranes in diabetes mellitus," J Pathol, vol. 200, pp. 537-46, Jul 2003.
[48] F. Winkler, S. V. Kozin, R. T. Tong, S. S. Chae, M. F. Booth, I. Garkavtsev, et al., "Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases," Cancer Cell, vol. 6, pp. 553-63, Dec 2004.
[49] V. P. Chauhan, T. Stylianopoulos, J. D. Martin, Z. Popovic, O. Chen, W. S. Kamoun, et al., "Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner," Nat Nanotechnol, vol. 7, pp. 383-8, Apr 8 2012.
[50] J. Segers, V. Di Fazio, R. Ansiaux, P. Martinive, O. Feron, P. Wallemacq, et al., "Potentiation of cyclophosphamide chemotherapy using the anti-angiogenic drug thalidomide: importance of optimal scheduling to exploit the 'normalization' window of the tumor vasculature," Cancer Lett, vol. 244, pp. 129-35, Nov 28 2006.
[51] S. P. Burr, A. S. Costa, G. L. Grice, R. T. Timms, I. T. Lobb, P. Freisinger, et al., "Mitochondrial Protein Lipoylation and the 2-Oxoglutarate Dehydrogenase Complex Controls HIF1alpha Stability in Aerobic Conditions," Cell Metab, vol. 24, pp. 740-752, Nov 8 2016.
[52] W. K. Rathmell and S. Chen, "VHL inactivation in renal cell carcinoma: implications for diagnosis, prognosis and treatment," Expert Rev Anticancer Ther, vol. 8, pp. 63-73, Jan 2008.
[53] Z. Liu, S. Gao, Y. Zhao, P. Li, J. Liu, P. Li, et al., "Disruption of tumor neovasculature by microbubble enhanced ultrasound: a potential new physical therapy of anti-angiogenesis," Ultrasound Med Biol, vol. 38, pp. 253-61, Feb 2012.
[54] M. Mazzone, D. Dettori, R. L. de Oliveira, S. Loges, T. Schmidt, B. Jonckx, et al., "Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization," Cell, vol. 136, pp. 839-851, Mar 6 2009.
[55] G. J. Cerniglia, N. Pore, J. H. Tsai, S. Schultz, R. Mick, R. Choe, et al., "Epidermal growth factor receptor inhibition modulates the microenvironment by vascular normalization to improve chemotherapy and radiotherapy efficacy," PLoS One, vol. 4, p. e6539, Aug 6 2009.
[56] S. Mitragotri, "Innovation - Healing sound: the use of ultrasound in drug delivery and other therapeutic applications," Nature Reviews Drug Discovery, vol. 4, pp. 255-260, Mar 2005.
[57] N. C. Nanda, R. Gramiak, and P. M. Shah, "Diagnosis of aortic root dissection by echocardiography," Circulation, vol. 48, pp. 506-13, Sep 1973.
[58] I. Lentacker, S. C. De Smedt, and N. N. Sanders, "Drug loaded microbubble design for ultrasound triggered delivery," Soft Matter, vol. 5, pp. 2161-2170, 2009.
[59] D. L. Miller and R. M. Thomas, "Ultrasound contrast agents nucleate inertial cavitation in vitro," Ultrasound Med Biol, vol. 21, pp. 1059-65, 1995.
[60] L. A. Crum and G. T. Reynolds, "Sonoluminescence Produced by Stable Cavitation," Journal of the Acoustical Society of America, vol. 78, pp. 137-139, 1985.
[61] J. E. Kennedy, "High-intensity focused ultrasound in the treatment of solid tumours," Nat Rev Cancer, vol. 5, pp. 321-7, Apr 2005.
[62] W. W. Roberts, T. L. Hall, K. Ives, J. S. Wolf, Jr., J. B. Fowlkes, and C. A. Cain, "Pulsed cavitational ultrasound: a noninvasive technology for controlled tissue ablation (histotripsy) in the rabbit kidney," J Urol, vol. 175, pp. 734-8, Feb 2006.
[63] S. Datta, C. C. Coussios, L. E. McAdory, J. Tan, T. Porter, G. De Courten-Myers, et al., "Correlation of cavitation with ultrasound enhancement of thrombolysis," Ultrasound Med Biol, vol. 32, pp. 1257-67, Aug 2006.
[64] R. J. Jeffers, R. Q. Feng, J. B. Fowlkes, J. W. Hunt, D. Kessel, and C. A. Cain, "Dimethylformamide as an Enhancer of Cavitation-Induced Cell-Lysis in-Vitro," Journal of the Acoustical Society of America, vol. 97, pp. 669-676, Jan 1995.
[65] S. P. Bao, B. D. Thrall, and D. L. Miller, "Transfection of a reporter plasmid into cultured cells by sonoporation in vitro," Ultrasound in Medicine and Biology, vol. 23, pp. 953-959, 1997.
[66] K. Hynynen, N. McDannold, N. A. Sheikov, F. A. Jolesz, and N. Vykhodtseva, "Local and reversible blood-brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications," Neuroimage, vol. 24, pp. 12-20, Jan 1 2005.
[67] T. Terahara, S. Mitragotri, J. Kost, and R. Langer, "Dependence of low-frequency sonophoresis on ultrasound parameters; distance of the horn and intensity," Int J Pharm, vol. 235, pp. 35-42, Mar 20 2002.
[68] I. De Cock, E. Zagato, K. Braeckmans, Y. Luan, N. de Jong, S. C. De Smedt, et al., "Ultrasound and microbubble mediated drug delivery: acoustic pressure as determinant for uptake via membrane pores or endocytosis," J Control Release, vol. 197, pp. 20-8, Jan 10 2015.
[69] H. Grull and S. Langereis, "Hyperthermia-triggered drug delivery from temperature-sensitive liposomes using MRI-guided high intensity focused ultrasound," J Control Release, vol. 161, pp. 317-27, Jul 20 2012.
[70] D. M. Skyba, R. J. Price, A. Z. Linka, T. C. Skalak, and S. Kaul, "Direct in vivo visualization of intravascular destruction of microbubbles by ultrasound and its local effects on tissue," Circulation, vol. 98, pp. 290-3, Jul 28 1998.
[71] P. Cianci, H. W. Lueders, H. Lee, R. L. Shapiro, J. Sexton, C. Williams, et al., "Adjunctive hyperbaric oxygen therapy reduces length of hospitalization in thermal burns," J Burn Care Rehabil, vol. 10, pp. 432-5, Sep-Oct 1989.
[72] R. A. Gatenby, H. B. Kessler, J. S. Rosenblum, L. R. Coia, P. J. Moldofsky, W. H. Hartz, et al., "Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy," Int J Radiat Oncol Biol Phys, vol. 14, pp. 831-8, May 1988.
[73] W. L. Monsky, D. Fukumura, T. Gohongi, M. Ancukiewcz, H. A. Weich, V. P. Torchilin, et al., "Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor," Cancer Res, vol. 59, pp. 4129-35, Aug 15 1999.
[74] W. W. Zhu, Z. L. Dong, T. T. Fu, J. J. Liu, Q. Chen, Y. G. Li, et al., "Modulation of Hypoxia in Solid Tumor Microenvironment with MnO2 Nanoparticles to Enhance Photodynamic Therapy," Advanced Functional Materials, vol. 26, pp. 5490-5498, Aug 9 2016.
[75] S. M. Fix, V. Papadopoulou, H. Velds, S. K. Kasoji, J. N. Rivera, M. A. Borden, et al., "Oxygen microbubbles improve radiotherapy tumor control in a rat fibrosarcoma model - A preliminary study," PLoS One, vol. 13, p. e0195667, 2018.
[76] J. J. Kwan, M. Kaya, M. A. Borden, and P. A. Dayton, "Theranostic oxygen delivery using ultrasound and microbubbles," Theranostics, vol. 2, pp. 1174-84, 2012.
[77] J. Sun, M. Yin, S. Zhu, L. Liu, Y. Zhu, Z. Wang, et al., "Ultrasound-mediated destruction of oxygen and paclitaxel loaded lipid microbubbles for combination therapy in hypoxic ovarian cancer cells," Ultrason Sonochem, vol. 28, pp. 319-26, Jan 2016.
[78] J. R. Eisenbrey, L. Albala, M. R. Kramer, N. Daroshefski, D. Brown, J. B. Liu, et al., "Development of an ultrasound sensitive oxygen carrier for oxygen delivery to hypoxic tissue," International Journal of Pharmaceutics, vol. 478, pp. 361-367, Jan 15 2015.
[79] A. Bisazza, P. Giustetto, A. Rolfo, I. Caniggia, S. Balbis, C. Guiot, et al., "Microbubble-mediated oxygen delivery to hypoxic tissues as a new therapeutic device," Conf Proc IEEE Eng Med Biol Soc, vol. 2008, pp. 2067-70, 2008.
[80] J. A. Feshitan, N. D. Legband, M. A. Borden, and B. S. Terry, "Systemic oxygen delivery by peritoneal perfusion of oxygen microbubbles," Biomaterials, vol. 35, pp. 2600-6, Mar 2014.
[81] A. Bhattacharya, M. Seshadri, S. D. Oven, K. Toth, M. M. Vaughan, and Y. M. Rustum, "Tumor vascular maturation and improved drug delivery induced by methylselenocysteine leads to therapeutic synergy with anticancer drugs," Clin Cancer Res, vol. 14, pp. 3926-32, Jun 15 2008.
[82] S. Bertuglia, "Increase in capillary perfusion following low-intensity ultrasound and microbubbles during postischemic reperfusion," Crit Care Med, vol. 33, pp. 2061-7, Sep 2005.
[83] B. P. Davidson, J. Hodovan, J. T. Belcik, F. Moccetti, A. Xie, A. Y. Ammi, et al., "Rest-Stress Limb Perfusion Imaging in Humans with Contrast Ultrasound Using Intermediate-Power Imaging and Microbubbles Resistant to Inertial Cavitation," J Am Soc Echocardiogr, vol. 30, pp. 503-510 e1, May 2017.
[84] J. Liu, S. Liao, B. Diop-Frimpong, W. Chen, S. Goel, K. Naxerova, et al., "TGF-beta blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma," Proc Natl Acad Sci U S A, vol. 109, pp. 16618-23, Oct 9 2012.
[85] N. M. Siafakas, M. Jordan, H. Wagner, E. C. Breen, H. Benoit, and P. D. Wagner, "Diaphragmatic angiogenic growth factor mRNA responses to increased ventilation caused by hypoxia and hypercapnia," Eur Respir J, vol. 17, pp. 681-7, Apr 2001.
[86] R. T. Tong, Y. Boucher, S. V. Kozin, F. Winkler, D. J. Hicklin, and R. K. Jain, "Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors," Cancer Res, vol. 64, pp. 3731-6, Jun 1 2004.
[87] Y. Huang, T. Stylianopoulos, D. G. Duda, D. Fukumura, and R. K. Jain, "Benefits of vascular normalization are dose and time dependent--letter," Cancer Res, vol. 73, pp. 7144-6, Dec 1 2013.
[88] C. G. Willett, Y. Boucher, E. di Tomaso, D. G. Duda, L. L. Munn, R. T. Tong, et al., "Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer (vol 10, pg 145, 2004)," Nature Medicine, vol. 10, pp. 649-649, Jun 2004.
[89] Y. Y. Shen, Z. K. Pi, F. Yan, C. K. Yeh, X. J. Zeng, X. F. Diao, et al., "Enhanced delivery of paclitaxel liposomes using focused ultrasound with microbubbles for treating nude mice bearing intracranial glioblastoma xenografts," International Journal of Nanomedicine, vol. 12, pp. 5613-5629, 2017.
[90] F. Y. Yang, C. E. Ko, S. Y. Huang, I. F. Chung, and G. S. Chen, "Pharmacokinetic changes induced by focused ultrasound in glioma-bearing rats as measured by dynamic contrast-enhanced MRI," PLoS One, vol. 9, p. e92910, 2014.
[91] R. Alkins, A. Burgess, M. Ganguly, G. Francia, R. Kerbel, W. S. Wels, et al., "Focused ultrasound delivers targeted immune cells to metastatic brain tumors," Cancer Res, vol. 73, pp. 1892-9, Mar 15 2013.